BAF Complex Maintains Glioma Stem Cells in Pediatric H3K27M Glioma.
| Title: | BAF Complex Maintains Glioma Stem Cells in Pediatric H3K27M Glioma. |
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| Authors: | Panditharatna E; Department of Pediatric Oncology, Dana-Farber Boston Children's Cancer and Blood Disorders Center, Boston, Massachusetts.; Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts.; Marques JG; Department of Pediatric Oncology, Dana-Farber Boston Children's Cancer and Blood Disorders Center, Boston, Massachusetts.; Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts.; Wang T; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts.; Department of Medicine, Harvard Medical School, Boston, Massachusetts.; Trissal MC; Department of Pediatric Oncology, Dana-Farber Boston Children's Cancer and Blood Disorders Center, Boston, Massachusetts.; Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts.; Liu I; Department of Pediatric Oncology, Dana-Farber Boston Children's Cancer and Blood Disorders Center, Boston, Massachusetts.; Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts.; Jiang L; Department of Pediatric Oncology, Dana-Farber Boston Children's Cancer and Blood Disorders Center, Boston, Massachusetts.; Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts.; Beck A; Center for Neuropathology, Ludwig Maximilian University of Munich, Munich, Germany.; Groves A; Department of Pediatric Oncology, Dana-Farber Boston Children's Cancer and Blood Disorders Center, Boston, Massachusetts.; Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts.; Dharia NV; Department of Pediatric Oncology, Dana-Farber Boston Children's Cancer and Blood Disorders Center, Boston, Massachusetts.; Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts.; Li D; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts.; Department of Medicine, Harvard Medical School, Boston, Massachusetts.; Hoffman SE; Department of Pediatric Oncology, Dana-Farber Boston Children's Cancer and Blood Disorders Center, Boston, Massachusetts.; Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts.; Kugener G; Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts.; Shaw ML; Department of Pediatric Oncology, Dana-Farber Boston Children's Cancer and Blood Disorders Center, Boston, Massachusetts.; Mire HM; Department of Pediatric Oncology, Dana-Farber Boston Children's Cancer and Blood Disorders Center, Boston, Massachusetts.; Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts.; Hack OA; Department of Pediatric Oncology, Dana-Farber Boston Children's Cancer and Blood Disorders Center, Boston, Massachusetts.; Dempster JM; Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts.; Lareau C; Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts.; Department of Pathology, Stanford University, Stanford, California.; Dai L; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts.; Department of Medicine, Harvard Medical School, Boston, Massachusetts.; Sigua LH; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts.; Department of Medicine, Harvard Medical School, Boston, Massachusetts.; Quezada MA; Department of Neurology, Stanford University School of Medicine, Stanford, California.; Stanton AJ; Department of Neurosurgery, Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.; Department of Pediatrics, Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.; Wyatt M; Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts.; Kalani Z; Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts.; Goodale A; Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts.; Vazquez F; Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts.; Piccioni F; Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts.; Merck Research Laboratories, Cambridge, Massachusetts.; Doench JG; Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts.; Root DE; Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts.; Anastas JN; Division of Newborn Medicine and Epigenetics Program, Department of Medicine, Boston Children's Hospital, Boston, Massachusetts.; Department of Neurosurgery and Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, Texas.; Jones KL; Lurie Family Imaging Center, Center for Biomedical Imaging in Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.; Conway AS; Department of Pediatric Oncology, Dana-Farber Boston Children's Cancer and Blood Disorders Center, Boston, Massachusetts.; Stopka S; Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.; Department of Radiology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.; Regan MS; Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.; Department of Radiology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.; Liang Y; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts.; Department of Medicine, Harvard Medical School, Boston, Massachusetts.; Seo HS; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts.; Department of Medicine, Harvard Medical School, Boston, Massachusetts.; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts.; Song K; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts.; Department of Medicine, Harvard Medical School, Boston, Massachusetts.; Bashyal P; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts.; Department of Medicine, Harvard Medical School, Boston, Massachusetts.; Jerome WP; Department of Pediatric Oncology, Dana-Farber Boston Children's Cancer and Blood Disorders Center, Boston, Massachusetts.; Mathewson ND; Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts.; Department of Microbiology and Immunobiology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts.; Department of Neurology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts.; Dhe-Paganon S; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts.; Department of Medicine, Harvard Medical School, Boston, Massachusetts.; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts.; Suvà ML; Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.; Klarman Cell Observatory, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts.; Carcaboso AM; Developmental Tumor Biology Laboratory, Hospital Sant Joan de Déu, Esplugues de Llobregat, Barcelona, Spain.; Lavarino C; Developmental Tumor Biology Laboratory, Hospital Sant Joan de Déu, Esplugues de Llobregat, Barcelona, Spain.; Mora J; Developmental Tumor Biology Laboratory, Hospital Sant Joan de Déu, Esplugues de Llobregat, Barcelona, Spain.; Nguyen QD; Lurie Family Imaging Center, Center for Biomedical Imaging in Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.; Ligon KL; Department of Pediatric Oncology, Dana-Farber Boston Children's Cancer and Blood Disorders Center, Boston, Massachusetts.; Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts.; Department of Pathology, Dana-Farber Cancer Institute, Boston, Massachusetts.; Department of Pathology, Boston Children's Hospital, Boston, Massachusetts.; Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts.; Shi Y; Division of Newborn Medicine and Epigenetics Program, Department of Medicine, Boston Children's Hospital, Boston, Massachusetts.; Ludwig Institute for Cancer Research, Oxford Branch, Oxford University, Oxford, United Kingdom.; Agnihotri S; Department of Neurosurgery, Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.; Department of Pediatrics, Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.; Agar NYR; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts.; Department of Medicine, Harvard Medical School, Boston, Massachusetts.; Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.; Department of Radiology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.; Stegmaier K; Department of Pediatric Oncology, Dana-Farber Boston Children's Cancer and Blood Disorders Center, Boston, Massachusetts.; Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts.; Stiles CD; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts.; Department of Medicine, Harvard Medical School, Boston, Massachusetts.; Monje M; Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, California.; Golub TR; Department of Pediatric Oncology, Dana-Farber Boston Children's Cancer and Blood Disorders Center, Boston, Massachusetts.; Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts.; Qi J; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts.; Department of Medicine, Harvard Medical School, Boston, Massachusetts.; Filbin MG; Department of Pediatric Oncology, Dana-Farber Boston Children's Cancer and Blood Disorders Center, Boston, Massachusetts.; Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts. |
| Source: | Cancer discovery [Cancer Discov] 2022 Dec 02; Vol. 12 (12), pp. 2880-2905. |
| Publication Type: | Editorial; Research Support, Non-U.S. Gov't; Research Support, N.I.H., Extramural; Comment |
| Language: | English |
| Journal Info: | Publisher: American Association for Cancer Research Country of Publication: United States NLM ID: 101561693 Publication Model: Print Cited Medium: Internet ISSN: 2159-8290 (Electronic) Linking ISSN: 21598274 NLM ISO Abbreviation: Cancer Discov Subsets: MEDLINE |
| Imprint Name(s): | Original Publication: Philadelphia, PA : American Association for Cancer Research |
| MeSH Terms: | Glioma*/genetics ; Epigenome*; Transcription Factors/genetics ; Transcription Factors/metabolism ; Neoplastic Stem Cells/metabolism ; Mammals/genetics ; Mammals/metabolism ; DNA Helicases/genetics ; Nuclear Proteins/genetics ; Animals ; Humans ; Mutation |
| Abstract: | Diffuse midline gliomas are uniformly fatal pediatric central nervous system cancers that are refractory to standard-of-care therapeutic modalities. The primary genetic drivers are a set of recurrent amino acid substitutions in genes encoding histone H3 (H3K27M), which are currently undruggable. These H3K27M oncohistones perturb normal chromatin architecture, resulting in an aberrant epigenetic landscape. To interrogate for epigenetic dependencies, we performed a CRISPR screen and show that patient-derived H3K27M-glioma neurospheres are dependent on core components of the mammalian BAF (SWI/SNF) chromatin remodeling complex. The BAF complex maintains glioma stem cells in a cycling, oligodendrocyte precursor cell-like state, in which genetic perturbation of the BAF catalytic subunit SMARCA4 (BRG1), as well as pharmacologic suppression, opposes proliferation, promotes progression of differentiation along the astrocytic lineage, and improves overall survival of patient-derived xenograft models. In summary, we demonstrate that therapeutic inhibition of the BAF complex has translational potential for children with H3K27M gliomas.; Significance: Epigenetic dysregulation is at the core of H3K27M-glioma tumorigenesis. Here, we identify the BRG1-BAF complex as a critical regulator of enhancer and transcription factor landscapes, which maintain H3K27M glioma in their progenitor state, precluding glial differentiation, and establish pharmacologic targeting of the BAF complex as a novel treatment strategy for pediatric H3K27M glioma. See related commentary by Beytagh and Weiss, p. 2730. See related article by Mo et al., p. 2906.; (©2022 The Authors; Published by the American Association for Cancer Research.) |
| Comments: | Comment in: Cancer Discov. 2022 Dec 2;12(12):2906-2929. doi: 10.1158/2159-8290.CD-21-1492.. (PMID: 36305747); Comment on: Cancer Discov. 2022 Dec 2;12(12):2906-2929. doi: 10.1158/2159-8290.CD-21-1492.. (PMID: 36305747); Comment in: Cancer Discov. 2022 Dec 2;12(12):2730-2732. doi: 10.1158/2159-8290.CD-22-1030.. (PMID: 36458436) |
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| Grant Information: | T32 EB025823 United States EB NIBIB NIH HHS; T32 CA136432 United States CA NCI NIH HHS; R35 CA210104 United States CA NCI NIH HHS; P41 EB015898 United States EB NIBIB NIH HHS; T32 GM007753 United States GM NIGMS NIH HHS; R35 CA210030 United States CA NCI NIH HHS; T32 GM144273 United States GM NIGMS NIH HHS; P41 EB028741 United States EB NIBIB NIH HHS; P50 CA165962 United States CA NCI NIH HHS; U54 CA210180 United States CA NCI NIH HHS; DP2 NS127705 United States NS NINDS NIH HHS |
| Substance Nomenclature: | 0 (Transcription Factors); EC 3.6.1.- (SMARCA4 protein, human); EC 3.6.4.- (DNA Helicases); 0 (Nuclear Proteins) |
| Entry Date(s): | Date Created: 20221028 Date Completed: 20221205 Latest Revision: 20240509 |
| Update Code: | 20260130 |
| PubMed Central ID: | PMC9716260 |
| DOI: | 10.1158/2159-8290.CD-21-1491 |
| PMID: | 36305736 |
| Database: | MEDLINE |
Editorial; Research Support, Non-U.S. Gov't; Research Support, N.I.H., Extramural; Comment